The present invention relates to new benzamidine derivatives which can be orally administrated to exhibit a strong anticoagulant effect by reversibly inhibiting activated blood-coagulation factor X; anticoagulants containing them as active ingredients; and agents for preventing or treating diseases caused by thrombi or emboli. These diseases include, for example, cerebrovascular disorders such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral obliteration; deep vein thrombosis; disseminated intravascular coagulation syndrome; thrombus formation after an artificial blood vessel-forming operation or artificial valve substitution; re-occlusion and re-stenosis after a coronary bypass-forming operation; re-occlusion and re-stenosis after reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation.
As the habit of life is being westernized and people of advanced ages are increasing in Japan, thrombotic and embolismic patients such as those suffering from myocardial infarction, cerebral thrombosis and peripheral thrombosis are increasing in number year by year, and the treatment of patients with these diseases is becoming more and more important in the society. Anticoagulation treatment is included in the internal treatments for the remedy and prevention of thrombosis, like radiotherapy and antithrombocytic therapy.
Antithrombins were developed as thrombus-formation inhibitors in the prior art. However, it has been known that since thrombin not only controls the activation of fibrinogen to form fibrin, which is the last step of the coagulation reaction, but also deeply relates to the activation and coagulation of blood platelets, the inhibition of the action of thrombin causes a danger of causing hemorrhage. In addition, when antithrombins are orally administered, the bioavailability thereof is low. At present, no antithrombin which can be orally administered is available on the market.
Since the activated blood coagulation factor X is positioned at the juncture of an exogenous coagulation cascade reaction and an endogenous coagulation cascade reaction and in the upstream of thrombin, it is possible to inhibit the coagulation system more efficiently and specifically, than the thrombin inhibition, by inhibiting the factor X (THROMBOSIS RESEARCH, Vol. 19, pages 339 to 349; 1980).
The object of the present invention is to provide compounds having an excellent effect of inhibiting the effect of activated blood coagulation factor X.
Another object of the present invention is to provide compounds having an effect of specifically inhibiting the effect of activated blood coagulation factor X, which can be orally administered.
Still another object of the present invention is to provide a blood-coagulation inhibitor or an agent for preventing or treating thrombosis of embolism, which contains one of the above-described compounds.
After intensive investigations made under these circumstances, the inventors have found that specified new benzamidine derivatives have an excellent effect of inhibiting activated blood coagulation factor X and are usable for preventing and treating various diseases caused by thrombi and emboli. The present invention has been completed on the basis of this finding.
Namely, the present invention provides benzamidine derivatives of following general formula (1-1), (1-2), (1-3) or (1-4) or pharmaceutically acceptable salts thereof, and blood coagulation inhibitors containing them as the active ingredients: 
In general formula (1-1), L represents an organic group of following formulae (2) to (5): 
In formulae (2), (3) and (5), W represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to 10 carbon atoms or an aralkyl group having 5 to 12 carbon atoms, one of D and Dxe2x80x2 in formula (3) represents a bond to Y in general formula (1-1) and the other represents hydrogen atom.
In formula (2), X represents hydrogen atom, carboxyl group, an alkoxycarbonyl group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms which may have a substituent(s) or benzyl group which may have a substituent(s). The substituent is selected from among carboxyl group, alkoxycarbonyl groups having 2 to 8 carbon atoms, alkylsulfonyloxy groups having 1 to 6 carbon atoms, piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 7 to 14 carbon atoms, piperidylalkyl groups having 6 to 8 carbon atoms, iminoalkylpiperidylalkyl groups having 7 to 11 carbon atoms, alkoxycarbonylpiperidylalkyl groups having 8 to 15 carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, hydroxyl group, halogeno groups, indolyl group and alkyl groups having 1 to 3 carbon atoms. In formula (2), X and W may be bonded together to form a ring and, in this case, xe2x80x94Wxe2x80x94Xxe2x80x94 represents ethylene group, trimethylene group or tetramethylene group.
When L is an organic group of any of formulae (2) to (4), V1 represents hydrogen atom, benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, piperazinecarbonyl, cinnamoyl, piperidinecarbonyl, 4-methylthiazole-5-carbonyl, phenylacetyl, phenylthiocarbonyl or benzimidoyl group which may have a substituent(s), or an alkanesulfonyl group having 1 to 6 carbon atoms, which may have a substituent(s). When L is an organic group of formula (5), V1 represents an aryl group having 4 to 10 carbon atoms, which may have a substituent(s).
When L is an organic group of any of formulae (2) to (5) and V1 has a substituent, the substituent is selected from among carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, halogeno groups, amino group, mono- or dialkylamino groups having 1 to 6 carbon atoms, arylamino groups having 4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl groups having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl groups having 2 to 7 carbon atoms, N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms, piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbon atoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms, alkoxycarbonylalkyl groups having 3 to 8 carbon atoms, hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms, alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groups having 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group, trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms, arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having 5 to 12 carbon atoms, piperazinecarbonyl group, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6 to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms, iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon atoms, iminoalkylpiperidylinealkyl groups having 8 to 12 carbon atoms, guanidino group, dialkylguanidino groups having 3 to 5 carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoyl groups having 9 to 13 carbon atoms, 1-alkylpyridinio groups having 6 to 9 carbon atoms and groups of the following formulae: 
In formulae (6) and (7), A represents a halogeno group, and in formulae (8) and (9), B represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group or amino group.
Y represents any of following formulae (10) to (16):
xe2x80x94(CH2)nxe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(10)
xe2x80x94(CH2)nxe2x80x94Sxe2x80x94xe2x80x83xe2x80x83(11)
xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(12)
xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(13)

In formulae (10) and (11), n represents an integer of 0 to 2. In formula (16), R1 represents a hydrogen atom, a hydroxycarbonylalkyl group having 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8 carbon atoms or a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms.
Z1 represents a group of any of following formulae (17) to (24): 
In formulae (17), (19), (21) and (23), m represents an integer of 0 to 3. In formulae (17), (18) and (24), R2 represents hydroxyl group, an alkoxyl group having 1 to 5 carbon atoms, trifluoromethyl group, amino group or a mono- or dialkylamino group having 1 to 6 carbon atoms. In formula (19), R3 represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms or acetyl group. In formulae (20) to (230), R4 represents hydrogen atom or an alkyl group having 1 to 6 carbon atoms. In formulae (22) and (23), R5 represents hydrogen atom or an alkyl group having 1 to 6 carbon atoms. In formula (24), R6 represents a halogeno group: 
wherein Z11 represents carboxyethyl group, ethoxycarbonylethyl group, hydroxymethyl group or hydroxypropyl group, and E represents an oil-soluble organic group 
In general formula (1-3), L represents an organic group of any of formulae (2) to (5) in above general formula (1-1). In formulae (2), (3) and (5), W is as defined in above general formula (1-1). In general formula (2), X is as defined in above general formula (1-1),
When L represents an organic group of formulae (2) to (4), V2 represents benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, phenylthiocarbonyl or benzimidoyl group having a substituent. When L is an organic group of formula (5), V2 represents an aryl group having 4 to 10 carbon atoms, which may have a substituent.
When L represents an organic group of formulae (2) to (5), the substituents of V2 include trialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoyl groups having 9 to 13 carbon atoms and 1-alkylpyridinio groups having 6 to 9 carbon atoms.
Y is represented by any of formulae (10) to (16) in above general formula (1-1), wherein n represents an integer of 1 or 2, and R1 is as defined above.
Z2 represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group or a group of following formula (13-2): 
In formula (13-2), R22 represents carboxyl group or an alkoxycarbonyl group having 2 to 5 carbon atoms. 
In general formula (1-4), L2 represents an organic group represented by formulae (2) to (4) in general formula (1-1), and W in formulae (2) and (3) and X in formula (2) are each as defined in above general formula (1-1),
when L2 represents an organic group of formulae (2) to (4), V1 is as defined in above general formula (1-1), and when V1 has a substituent, the substituent is as defined in above general formula (1-1), and
Y2 is any of formulae (10) and (11) in above general formula (1-1), and R3 represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms or acetyl group.
The alkyl groups in the present invention may be branched or have a ring. For example, the alkyl groups include cyclohexylmethyl group or the like. The term xe2x80x9carylxe2x80x9d herein involves not only aromatic cyclic hydrocarbon groups but also aromatic heterocyclic groups having 1 to 3 hetero-atoms selected from among O, N and S. Examples of the aryl groups include phenyl, pyridyl, imidazolyl and pyrrolyl groups. An example of the arylalkenyl groups is 2-(4-pyridyl)vinyl group. Dialkylamidino groups include N,N-dialkylamidino groups and N,Nxe2x80x2-dialkylamidino groups. The two alkyl groups in the dialkylcarbamoyl groups, dialkylamidino groups, dialkylamino groups, dialkylaminoalkyl groups, dialkylaminosulfonyl groups and dialkylguanidino groups may be bonded together to form a ring. In those groups, one of CH2""s may be replaced with O, NH or S. For example, dialkylcarbamoyl groups include, for example, 1-pyrrolidinecarbonyl group; dialkylamidino groups include, for example, 2-imidazoline-2-yl group and (pyrrolidine-1-yl)(imino)methyl group; and dialkylguanidino groups include, for example, imidazoline-2-amino group. The acyl groups include not only alkylcarbonyl groups but also arylcarbonyl groups. For example, the acyl groups having 1 to 8 carbon atoms include benzoyl group. The alkoxyl groups include, for example, cyclohexyloxy group and phenoxyl group. The alkoxycarbonyl groups include benzyloxycarbonyl group, etc. Preferred 1-alkylpyridinio groups having 6 to 9 carbon atoms are all of those having 6 carbon atoms or 7 to 9 carbon atoms.
The compounds of the present invention may have an asymmetric carbon atom. These compounds include mixtures of various stereoisomers such as geometrical isomers, tautomers and optical isomers, and those isolated therefrom. The amidino group in the compounds of the present invention may be replaced with a suitable substituent which can be changed into the amidino group in vivo. For example, hydrogen atom bonded to nitrogen atom having double bond in amidino group bonded to the benzene ring in general formulae (1-1) to (1-4) is replaced with hydroxyl group, an alkoxyl group such as ethoxyl group, amino group, carboxyl group, an alkoxycarbonyl group such as ethoxycarbonyl group, an alkylsulfonyl group such as ethylsulfonyl group, carbamoyl group, carbamoyl group in which one or two hydrogen atoms are replaced with an alkyl group such as diethoxycarbamoyl group, formyl group, an acyl group such as acetyl group or an alkylcarboxyl group such as acetoxyl group.
L in general formula (1-1) is preferably that represented by formulae (2) to (4), more preferably formulae (2) and (4), and particularly formula (2).
W is preferably hydrogen atom or an alkyl group having 1 to 6 carbon atoms. W is particularly preferably hydrogen atom. X is preferably hydrogen atom, a carboxyalkyl group having 2 or 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 10 carbon atoms. W is particularly preferably hydrogen atom, carboxymethyl group or ethoxycarbonylmethyl group. X is preferably hydrogen atom, carboxyl group, an alkyl group having 1 to 3 carbon atoms, which may have a substituent(s), or benzyl group which may have a substituent(s). X is particularly preferably hydrogen atom or an alkyl group having one carbon atom and a substituent.
When X has a substituent, the substituent is, for example, benzyloxycarbonyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, ethanesulfonyloxy group, butanesulfonyloxy group, 4-piperidyloxy group, 1-acetimidoyl-4-piperidyloxy group, (1-acetimidoyl-4-piperidyl)methyl group, 1-acetimidoyl-3-pyrrolidyloxy group, isopropyl group, 3-indolyl group or iodine atom. In these substituents, carboxyl group is particularly preferred.
V1 is preferably benzoyl group which may have a substituent(s), piperidinecarbonyl group which may have a substituent(s) or pyridinecarbonyl group which may have a substituent(s). V1 is more preferably benzoyl group having a substituent(s) or piperidinecarbonyl group having a substituent.
When V1 has a substituent, the substituent is preferably 4-piperydyloxy group, 1-acetimidoyl-4-piperidyloxy group, 4-pyridyl group, tetrafluoropyridyl group, 3,5-dichloropyridyl group, 6-chloropyridazyl group, pyridazyl group, 2-chloropyrimidyl group, pyrimidyl group, 4-pyridine-4-ylmethyl group or 4-pyridylcarbonyl group. The substituent is more preferably 1-acetimidoyl-4-piperidyloxy group or 4-pyridyl group. V1 is particularly preferably either 1-acetimidoyl-4-piperidyloxybenzoyl group or 1-(4-pyridyl)-piperizine-4-carbonyl group.
It is more preferred that Y represents an organic group of formula (10) wherein n is an integer of 1.
Z1 is preferably a group represented by formula (17), (19), (21) or (23). Z1 is more preferably carboxyethyl group, ethoxycarbonylethyl group, sulfoethyl group, phosphonoethyl group, diethoxyphosphorylethyl group, monoethoxyhydroxyphosphorylethyl group, hydroxymethyl group or hydroxypropyl group. Z1 is particularly preferably carboxyethyl group, ethoxycarbonylethyl group, hydroxymethyl group or hydroxypropyl group.
In the compounds of general formula (1-1), benzamidine derivatives of general formula (1-1) wherein L represents an organic group of formula (2), W represents hydrogen atom and X represents any of hydrogen atom, carboxymethyl group and ethoxycarbonylmethyl group, or pharmaceutically acceptable salts thereof are preferred.
Benzamidine derivatives of general formula (1-1) wherein Y represents an organic group of formula (10), and n represents an integer of 1 or 2 or pharmaceutically acceptable salts thereof are preferred.
Preferred compounds are benzamidine derivatives of general formula (1-1) wherein V1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group, 1-(4-pyridyl)-piperidine-4-carbonyl group, 1-(2,3,5,6-tetrafluoropyridine-4-yl)-piperidine-4-carbonyl group, 1-(3,5-dichloropyridine-4-yl)-piperidine-4-carbonyl group, 1-(6-chloropyridazine-3-yl)-piperidine-4-carbonyl group, 1-(pyridazine-3-yl)-piperidine-4-carbonyl group, 1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group, 1-(pyrimidine-4-yl)-piperidine-4-carbonyl group, 1-(4-pyridine-4-ylmethyl)-piperidine-4-carbonyl group, 1-(4-pyridine-4-carbonyl)-piperidine-4-carbonyl group or 4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl group, or pharmaceutically acceptable salts thereof.
Preferred compounds are benzamidine derivatives of general formula (1-1) wherein Z1 represents carboxyethyl group, ethoxycarbonylethyl group, carboxyvinyl group, ethoxycarbonylvinyl group, carbamoylethyl group, carbamoylvinyl group, carboxyl group, ethoxycarbonyl group, methoxycarbonyl group, sulfoethyl group, sulfovinyl group, phosphonovinyl group, diethoxyphosphorylvinyl group, monoethoxyhydroxyphosphorylvinyl group, phosphonoethyl group, diethoxyphosphorylethyl group, monoethoxyhydroxyphosphorylethyl group, hydroxymethyl group, hydroxypropyl group or acetoxymethyl group, or pharmaceutically acceptable salts thereof.
Preferred compounds are benzamidine derivatives of general formula (1-1) wherein Y represents an organic group of formula (10), V1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group or 1-(4-pyridyl)piperidine-4-carbonyl group and Z1 represents carboxyethyl group, ethoxycarbonylethyl group, sulfoethyl group, hydroxymethyl group or hydroxypropyl group, or pharmaceutically acceptable salts thereof.
Preferred compounds are benzamidine derivatives of general formula (1-1) wherein L represents an organic group of formulae (2) to (4) and Y represents an organic group of formulae (10) to (13), or pharmaceutically acceptable salts thereof.
Preferred benzamidine derivatives are those of general formula (1-1) wherein, when L represents an organic group of formulae (2) to (4), V1 represents hydrogen atom, benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, phenylthiocarbonyl or benzimidoyl group which may have a substituent or an alkanesulfonyl group having 1 to 6 carbon group, which may have a substituent; when L represents an organic group of formula (5), V1 represents an aryl group having 4 to 10 carbon atoms, which may have a substituent(s);
when L represents an organic group of formulae (2) to (5), the substituents of V1 are carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, halogeno groups, amino group, mono- or dialkylamino groups having 1 to 6 carbon atoms, arylamino groups having 4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl groups having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl groups having 2 to 7 carbon atoms, N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms, piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms, pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbon atoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms, alkoxycarbonylalkyl groups having 3 to 8 carbon atoms, hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms, alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groups having 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group, trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms, arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having 5 to 12 carbon atoms, piperazinecarbonyl group, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6 to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms, iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms, piperidylidenealkyl groups having 6 to 9 carbon atoms, iminoalkylpiperidylidenealkyl groups having 8 to 12 carbon atoms, guanidino groups, dialkylguanidino groups having 3 to 5 carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms and monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms,
Y represents a group of formulae (10) to (16), and n in formulae (10) and (11) represents an integer of 1 or 2,
Z1 represents a group of formulae (17) and (18) wherein m represents an integer of 1 to 3, and R2 represents hydroxyl group, an alkoxyl group having 1 to 5 carbon atoms, amino group or a mono- or dialkylamino group having 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof.
Preferably, L represents an organic group of formula (2), W represents hydrogen atom and X represents hydrogen atom, carboxymethyl group or ethoxycarbonylmethyl group.
Preferably, Y represents an organic group of formula (10) and n represents an integer of 1.
Preferably, V1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group or 1-(4-pyridyl)-piperizine-4-carbonyl group.
Preferably, Z1 represents carboxyethyl group, ethoxycarbonylethyl group, carboxyvinyl group, ethoxycarbonylvinyl group, carbamoylethyl group or carbamoylvinyl group.
Preferably, L represents an organic group of formula (2), Y represents an organic group of formula (10), V1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group or 1-(4-pyridyl)-piperizine-4-carbonyl group, and Z1 represents carboxyethyl group, ethoxycarbonylethyl group or carbamoylethyl group.
Benzamidine derivatives of general formula (1-2) and pharmaceutically acceptable salts thereof have an effect of inhibiting the activated blood coagulation factor X. In general formula (1-2), Z11 is as defined above, and E represents an oil-soluble organic group which, together with other groups in general formula (1-2), imparts an effect of inhibiting the activated blood coagulation factor X to the compounds of general formula (1-2). The effect on the activated blood coagulation factor X can be determined by a method described in Examples in this specification. Groups E are those having a bonding group capable of bonding to the benzene ring, a terminal aromatic group and/or a heterocyclic group. They are organic groups which are, as a whole, soluble in an oil. The bonding groups herein include aliphatic organic groups, which may contain an oxygen atom or nitrogen atom, such as alkylene groups and hydroxyalkylene groups. The terminal aromatic groups and/or heterocyclic groups include phenyl group, naphthyl group, piperidine group, pyridine group, etc. The oil-soluble organic groups are preferably the same as xe2x80x94Yxe2x80x94Lxe2x80x94V1 in above formula (1-1) wherein L represents an organic group of formula (2), Y represents an organic group of formula (10) and V1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group or 1-(4-pyridyl)-piperidine-4-carbonyl group.
Preferred groups L and more preferred groups L in general formula (1-3) are the same as those described above with reference to general formula (1-1). When L is an organic group of above formulae (2) to (5), V2 and substituents thereof are as described above. Particularly preferred V2 is benzoyl group having a substituent which is selected from among trialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoyl groups having 9 to 13 carbon atoms and 1-alkylpyridinio groups having 6 to 9 carbon atoms.
V2 is preferably 4-(3,4-dimethoxybenzoyl)benzoyl group, 1-(1-methylpyridinium-4-yl)piperizine-4-carbonyl group or 4-(1-methyl-2-imidazoline-2-yl)benzoyl group.
Y is any of above formulae (10) to (16) in general formula (1-1), and Z2 is hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group or a group of formula (13-2). Preferred groups Y are the same as those in general formula (1-1). A preferred group Z2is that of formula (13-2) wherein R22 is carboxyl group.
Preferably L in general formula (1-3) represents an organic group of formula (2), W represents hydrogen atom, X represents hydrogen atom, V2 represents 4-(3,4-dimethoxybenzoyl)benzoyl group, 1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl group or 4-(1-methyl-2-imidazoline-2-yl)benzoyl group and Z2 represents hydrogen atom or 2-carboxy-2-oxoethyl group.
Preferably L in general formula (1-3) represents an organic group of formula (2), W represents hydrogen atom, X represents hydrogen atom, V2 represents 4-(1-methyl-2-imidazoline-2-yl)benzoyl group and Z2 represents 2-carboxy-2-oxoethyl group.
Preferred groups W, X and V1 and more preferred groups W, X and V1 in general formula (1-4) are the same as those described above with reference to general formula (1-1). L2 is preferably that represented by formula (2) or (4). More preferably, L2 is that represented by formula (2).
Y2 is preferably that represented by formula (10), and R3 is preferably hydrogen atom, an alkyl group having 1 to 3 carbon atoms or acetyl group. R3 is more preferably hydrogen atom.
In general formula (1-4), preferably, L2 represents an organic group of formula (2), W represents hydrogen atom and X represents any of hydrogen atom, carboxymethyl group and ethoxycarbonylmethyl group.
In general formula (1-4), preferably Y2 represents an organic group of formula (10), and n represents an integer of 1 or 2. Particularly preferably, n represents an integer of 1.
In general formula (1-4), V1 is preferably 1-acetimidoyl-4-piperidyloxybenzoyl group, 1-(4-pyridyl)-piperidine-4-carbonyl group, 1-(2,3,5,6-tetrafluoropyridine-4-yl)-piperidine-4-carbonyl group, 1-(3,5-dichloropyridine-4-yl)-piperidine-4-carbonyl group, 1-(6-chloropyridazine-3-yl)-piperidine-4-carbonyl group, 1-(pyridazine-3-yl)-piperidine-4-carbonyl group, 1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group, 1-(pyrimidine-4-yl)-piperizine-4-carbonyl group, 1-(4-pyridine-4-ylmethyl)-piperidine-4-carbonyl group, 1-(4-pyridine-4-carbonyl)-piperidine-4-carbonyl group or 4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl group.
In general formula (1-4), preferably L2 represents an organic group, Y represents an organic group of formula (10), V1 represents 1-acetimidoyl-4-piperidyloxybenzoyl group or 1-(4-pyridyl)piperizine-4-carbonyl group and R3 represents hydrogen atom.
Typical processes for producing compounds of the present invention are as follows:
A compound (27) can be obtained by reacting an aminoalkyl halide (25), in which nitrogen is protected with benzyloxycarbonyl group, t-butoxycarbonyl group base, with 3-hydroxy-4-iodobenzonitrile (26) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide. An acrylic acid derivative (28) can be derived from the obtained compound (27) by, for example, condensing it with ethyl acrylate or the like by, for example, Heck reaction in dimethylformamide or the like as the solvent. The protecting group on the nitrogen of the obtained compound (28) can be removed in, for example, an acidic solution such as 4 N solution of hydrogen chloride in dioxane to obtain a corresponding amine (29). 
Prot in the above formulae represents a protecting group such as Boc group or Z group, and Hal represents a halogen atom.
Then, the amine (29) is reacted with a condensing agent in the presence of a base such as triethylamine in a solvent such as dimethylformamide. The amine is thus condensed with a carboxylic acid to obtain an amide (30). 
Cyano group in the amide (30) obtained as described above can be converted into amidino group by reacting amide (30) with an alcohol such as ethanol containing a hydrogen halide such as hydrogen chloride and then reacting the reaction product with an ammonium salt such as ammonium carbonate. By these reaction steps, benzamidine derivative (31) of general formula (1-1) wherein L is represented by formula (2), Y is represented by formula (10) and Z is represented by formula (18) can be produced. 
Benzamidine derivative (32) of general formula (1-1) wherein L is represented by formula (2), Y is represented by formula (10) and Z is represented by formula (17) can be produced by reacting benzamidine derivative (31) in the presence of a catalyst such as palladium/carbon in an alcohol such as methanol as the solvent in hydrogen atmosphere and then hydrolyzing the reaction product in an acidic aqueous solution such as concentrated hydrochloric acid. 
The compounds produced as described above and salts thereof can be isolated by the purification by a well-known method such as extraction, concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, redissolution or various chromatographic techniques.
The salts of the benzamidine derivatives of the present invention are pharmaceutically acceptable ones such as salts of them with mineral acids, e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids, e. g. formic acid, acetic acid, trifluoroacetic aid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid.
The compounds and salts thereof of the present invention are administered as they are or in the form of various medicinal compositions to patients. The dosage forms of the medicinal compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets and depots. They can be prepared with ordinary preparation assistants by an ordinary method. For example, the tablets are prepared by mixing the benzamidine derivative, the active ingredient of the present invention, with any of known adjuvants such as inert diluents, e. g. lactose, calcium carbonate and calcium phosphate, binders, e. g. acacia, corn starch and gelatin, extending agents, e. g. alginic acid, corn starch and pre-gelatinized starch, sweetening agents, e. g. sucrose, lactose and saccharin, corrigents, e. g. peppermint and cherry, and lubricants, e. g. magnesium stearate, talc and carboxymethyl cellulose.
When the benzamidine derivatives and salts thereof of the present invention are used as the anticoagulants, they can be administered either orally or parenterally. The dose which varies depending on the age, body weight and conditions of the patient and the administration method is usually 0.01 to 1,000 mg, preferably 0.1 to 50 mg, a day for adults in the oral administration, and 1 xcexcg to 100 mg, preferably 0.01 to 10 mg, in the parenteral administration.